JP5588445B2 - Novel crystalline form of calcium 3-acetylaminopropane-1-sulfonate - Google Patents

Description

  The present invention relates to a novel crystalline form of calcium 3-acetylaminopropane-1-sulfonate, a process for its preparation and its use in medicine.

Calcium 3-acetylaminopropane-1-sulfonate, also referred to below as “active compound”, has the following chemical structure:

Calcium 3-acetylaminopropane-1-sulfonate is first described in DE 301 935 A1 and has been adopted as an active compound for the treatment of alcohol dependence. The use of this active compound in the treatment of tinnitus has also been described.
According to DE 301 935 A1, calcium 3-acetylaminopropane-1-sulfonate is a crystalline, colorless powder having a freezing point of approximately 270 ° C. and a water content of 3.6%. 7% and 6.8% nitrogen were measured (theoretical values were 10% and 7%).

Toffoli et al. Described the crystalline form of calcium 3-acetylaminopropane-1-sulfonate (P. Toffoli, N. Rodier, R. Ceolin, P. Ladure, G. Tran, Acta Crystallographica, Sect. C, Crystal Structure Communications, 1998, 44, 1493), this form is also referred to below as “Crystal Form I” or “Form I”. According to Toffoli et al., Form I is characterized by the following parameters: monoclinic, P2 ₁ / c, a = 5.4584Å, b = 18.949Å, c = 8.550Å, β = 105.49 °, V = 852.2 Å ³ .
The crystalline form of calcium 3-acetylaminopropane-1-sulfonate described by Toffoli et al. Corresponds to the crystalline form of calcium 3-acetylaminopropane-1-sulfonate present in pharmaceuticals on the market.

DE3019350A1

P. Toffoli, N. Rodier, R. Ceolin, P. Ladure, G. Tran, Acta Crystallographica, Sect. C, Crystal Structure Communications, 1998, 44, 1493

Here, it is found that calcium 3-acetylaminopropane-1-sulfonate is also present in another crystal form, which is also referred to below as “form II” or “crystal form II”. Form II has a freezing point of approximately 364 ° C., and therefore this freezing point is significantly higher than that described in DE 3019350 A1.
Surprisingly, the newly discovered Form II was found to be thermodynamically more stable than Form I.
The elution rate of the active compound is determined inter alia by its crystalline form. If the active compound is present in various crystalline forms and is to be the active pharmaceutical compound, it is advantageous to use a thermodynamically more stable form of the active compound. This is because the thermodynamically more unstable (metastable) form present in a pharmaceutical is in a more thermodynamically stable form, especially during storage of the drug, until it is used by the patient after preparation of the drug. This is because it is basically possible to eliminate the change to.
Conversion from one crystal form to another means, inter alia, a change in the dissolution rate of the active compound, meaning that the original release of the active compound from the pharmaceutical is no longer reproducible. The change in the dissolution rate of the active compound is unfortunately the absorption of the active compound present in the gastrointestinal tract from the drug at a predetermined rate and amount after it has been administered to the patient. Results in that it is not done, meaning that its bioavailability, and therefore its effectiveness, is no longer guaranteed. Therefore, the use of medicinal products containing active compounds is uncertain as a whole.
The active compound according to DE 30 19 350 A1 contains water of crystallization (estimated 3.6%), but this is not present in Form II.

As already indicated, crystalline form II of the active compound is thermodynamically more stable than crystalline form I. Therefore, in the suspension conversion experiment from crystal form I, rearrangement to crystal form II occurs. Furthermore, a significantly lower enthalpy is produced from −13.1 ± 0.2 J / g in crystalline form I to 16.2 ± 0.2 J / g in crystalline form II ((6.9 ± 0.4 J / g). g), in each case measured at 25 ° C. in water using a 2225 Thermometrics Solution calorimeter). Therefore, Form II has a lower Gibbs free enthalpy and is thermodynamically more stable than Form I.
Form II is obtained by stirring a suspension of crystals of Form I in which calcium 3-acetylaminopropane-1-sulfonate is suspended in a stable suspending medium and drying the resulting residue. Can be prepared. A stable suspending medium is a solvent in which the active compound can be dissolved, wherein the active compound is added to each solvent in the suspension in a weight ratio that exceeds the solubility limit of the active compound in the solvent. The active compound is thus mainly in solid form in suspension. Suitable suspending media are, for example, water, methanol, and / or tetrahydrofuran (THF), where water is particularly preferred.
Form I of the active compound can be obtained by methods shown in the prior art.
Crystal forms can be determined by standard methods such as CW Bunn, “Chemical Crystallography” 1948, Clarendon Press, London; or HP Klug, LE Alexander, “X-Ray Diffraction Procedures” 1974, John Wiley and Sons. , New York.

FIG. 1 shows an X-ray diffraction pattern of form I of the above material, and the resulting parameters are shown in Table 1 below.
Table 1

  Table 1: Bruker D5000 diffractometer, transmission mode, generator power 40 kV / 30 mA, Cu-Kα1 line (λ = 1.54Å), position detection element (3.3 kV), measurement range: 3-65 ° 2Θ, step size: 0.05 ° 2Θ, time / step: Form I X-ray diffraction pattern measured using 1.4 seconds. The diffraction pattern was background corrected through the recording range 3-65 ° 2Θ to determine the reflection intensity of the strongest reflection. For the Cu-Kα1 line used, the tolerance of the angle position is ± 0.1 ° 2Θ.

FIG. 2 shows the X-ray diffraction pattern of the active compound Form II, and the resulting parameters are summarized in Table 2 below.
Table 2

  Table 2: X-ray diffraction pattern of Form II. Measurement and evaluation were performed in the same manner as described in Table 1.

In a preferred embodiment, Form II is characterized by the X-ray data shown in Table 2a below. The data shown in Table 2a includes the reflection from Table 2 and an additional 6 reflections of even weaker intensity.
Table 2a

Table 2a: X-ray diffraction pattern of Form II. Measurement and evaluation were performed in the same manner as described in Table 1.
The present invention therefore relates to crystalline form II of calcium 3-acetylaminopropane-1-sulfonate characterized by the characteristic lattice spacing shown in Table 2.
The present invention also relates to the crystalline form II of calcium 3-acetylaminopropane-1-sulfonate characterized by the characteristic lattice spacing shown in Table 2a.
The invention further relates to crystalline form II of calcium 3-acetylaminopropane-1-sulfonate characterized by physical data according to at least one analytical method as described above and below.

When examined by single crystal X-ray diffraction, the following characteristic parameters occur for crystalline form II of calcium 3-acetylaminopropane-1-sulfonate: triclinic, P ₁ , a = 5. 54 °, b = 8.15 °, c = 9.76 °, α = 69.1 °, β = 84.3 °, γ = 89.4 °, V = 409.66 ° ³ (Oxford X calibur diffractometer (Mo K _(alpha ray), graphite monochromator, sapphire CCD, data evaluation using SHELX-97 software suite).
The invention further relates to the crystalline form II of calcium 3-acetylaminopropane-1-sulfonate characterized by the following parameters: P ₁ , a = 5.54 Å, b = 8.15 Å, c = 9.76 Å , Α = 69.1 °, β = 84.3 °, γ = 89.4 °, V = 409.66Å ³ .
The resulting crystal structure is shown in FIG. As is apparent, the crystal structure of Form II is free of water or other solvents.
“Form II consisting essentially of Form II” is used above and below to indicate that crystalline Form II comprises less than 5% by weight of Form I, preferably less than 2% by weight, particularly preferably less than 1% by weight. means.
The invention therefore further relates to calcium 3-acetylaminopropane-1-sulfonate essentially consisting of crystal form II.

The invention further relates to a process for the preparation of crystalline form II of the active compound, which is obtained by stirring crystals of crystalline form I of calcium 3-acetylaminopropane-1-sulfonate in a suspension medium. The residue is separated and dried.
The active compound can of course also be employed as a mixture of its crystalline forms II and I, where in each case 10%, 20%, 30%, 40%, 50%, 60% More than 70%, 70%, 80%, or 90% by weight of crystalline Form II may be present. According to the invention, preference is given to mixtures comprising crystalline form II in excess of 70% by weight, particularly preferably in excess of 80% by weight, particularly preferably in excess of 90% by weight.
Crystalline form II, as already described, is thermodynamically stable and is therefore particularly suitable as a pharmaceutical product. The invention therefore also relates to crystalline form II as a medicament.
The invention likewise relates to a pharmaceutical composition comprising crystalline form II.
The invention further relates to crystal form II for the preparation of a medicament.
The following examples illustrate this without limiting the invention.

X-ray powder diffraction pattern of crystalline form I of calcium 3-acetylaminopropane-1-sulfonate X-ray powder diffraction pattern of crystalline form II of calcium 3-acetylaminopropane-1-sulfonate Each crystal structure of calcium 3-acetylaminopropane-1-sulfonate; left: field along the a-axis; right: field along the c-axis FT-IR spectrum of form II of calcium 3-acetylaminopropane-1-sulfonate FT-Raman spectrum of form II of calcium 3-acetylaminopropane-1-sulfonate FT-IR spectrum of Form I of calcium 3-acetylaminopropane-1-sulfonate FT-Raman spectrum of form I of calcium 3-acetylaminopropane-1-sulfonate

[Example 1]
Preparation of calcium 3-acetylaminopropane-1-sulfonate crystal form II 3 g of calcium 3-acetylaminopropane-1-sulfonate was suspended in 2 mL of deionized water and stirred at room temperature for 7 days. The resulting suspension was filtered and dried.

[Example 2]
Analytical characterization of crystal form II obtained according to example 1 In order to characterize the crystal form of the crystal obtained according to example 1 (form II), infrared (FR-IR) and Raman spectra (FT- Raman) was recorded. FT-IR and FT-Raman were performed by standard methods as described in European Pharmacopoeia, 6th Edition, Chapters 2.02.24 and 2.02.48.
FT-IR spectroscopy was performed using a KBr compressed disc. The FT-IR spectrum measurement is shown in FIG. 4 and has the typical bands shown below (indicating IR wave number (cm ⁻¹ ± 2 cm ⁻¹ ) and their relative intensities). .
3311 cm ^-1 (m), 3106 cm ^-1 (m), 2955 cm ^-1 (m), 2888 cm ^-1 (m), 1637 cm ^-1 (s), 1568 cm ^-1 (s), 1470 cm ^-1 (m), 1449 cm ^-1 (m), 1417 cm ^-1 (m), 1380 cm ^-1 (m), 1302 cm ^-1 (m), 1274 cm ^-1 (m), 1223 cm ^-1 (s), 1191 cm ^-1 (s), 1172 cm ^-1 (s), 1076 cm ^-1 (s), 1066 cm ^-1 (s), 953 cm ^-1 (m), 804 cm ^-1 (m ), 744 cm ^-1 (m), 706 cm ^-1 (m), 642 cm ^-1 (m), 611 cm ^-1 (m), 598 cm ^-1 (m), 556 cm ^-1 (m), 529 cm ^-1 (m), 424 cm ^-1 (m).
Measurement conditions: FT-IR spectrophotometer, Bruker Vector 22, spectral resolution 2 cm ⁻¹ , 32 scans.
Evaluation: The resulting FT-IR spectra were background corrected (Bruker OPUS software. Bands were split as follows based on their transmission.
s = strong (transmission ≦ 20%)
m = moderate (20% <transmission ≦ 60%)
w = weak (transmission> 60%)

The measured FT-Raman spectrum is shown in FIG. 5 and has the following typical bands.
3310 cm ^-1 (w), 2981 cm ^-1 (m), 2937 cm ^-1 (s), 2877 cm ^-1 (m), 1637 cm ^-1 (m), 1480 cm ^-1 (m), 1453 cm ^-1 (m), 1419 cm ^-1 (m), 1392 cm ^-1 (m), 1345 cm ^-1 (m), 1310 cm ^-1 (m), 1300 cm ^-1 (w), 1244 cm ^-1 (w), 1226 cm ^-1 (m), 1169 cm ^-1 (m), 1109 cm ^-1 (m), 1070 cm ^-1 (s), 955 cm ^-1 (m), 805 cm ^-1 (m ), 649 cm ^-1 (m), 595 cm ^-1 (m), 553 cm ^-1 (m), 534 cm ^-1 (m), 487 cm ^-1 (m).
Raman band wavenumber (cm ⁻¹ ± 2 cm ⁻¹ ) and their relative intensities Measurement conditions: FT-Raman spectrophotometer, Bruker RFS 100, 1064 nm excitation, 500 mW, spectral resolution 1 cm ⁻¹ , 500 scans.
Evaluation: The Raman spectra obtained were vector normalized (vector-standardised) in the spectral range from 3600 cm ^-1 250 cm ^-1. Bands were divided as follows based on their intensities.
s = strong (relative Raman intensity ≧ 0.1)
m = moderate (0.1 <relative Raman intensity ≧ 0.025)
w = weak (relative Raman intensity <0.025)

[Example 3]
Analytical characterization of Form I For comparison purposes, the active compound Form I (Example 1 starting material) was analytically characterized and evaluated as in Example 2.
The FT-IR spectrum of Form I is shown in FIG. 6 and has the following parameters:
3312 cm ^-1 (m), 3123 cm ^-1 (w), 2980 cm ^-1 (w), 2937 cm ^-1 (m), 2878 cm ^-1 (w), 2864 cm ^-1 (w), 1658 cm ^-1 (s), 1577 cm ^-1 (s), 1453 cm ^-1 (m), 1441 cm ^-1 (m), 1370 cm ^-1 (m), 1298 cm ^-1 (s), 1234 cm ^-1 (s), 1219 cm ^-1 (s), 1199 cm ^-1 (s), 1160 cm ^-1 (s), 1083 cm ^-1 (m), 1064 cm ^-1 (s), 1018 cm ^-1 (m ), 946 cm ^-1 (m), 850 cm ^-1 (w), 789 cm ^-1 (m), 744 cm ^-1 (m), 625 cm ^-1 (m), 596 cm ^-1 (s), 545 cm ^-1 (m), 521 cm ^-1 (m), 490 cm ^-1 (w), 418 cm ^-1 (m).
The FT-Raman spectrum of Form I is described in FIG. 7 and is characterized by the following parameters:
3304 cm ^-1 (w), 2980 cm ^-1 (m), 2958 cm ^-1 (m), 2934 cm ^-1 (s), 2879 cm ^-1 (w), 1661 cm ^-1 (w), 1454 cm ^-1 (w), 1442 cm ^-1 (w), 1408 cm ^-1 (w), 1369 cm ^-1 (w), 1316 cm ^-1 (w), 1298 cm ^-1 (m), 1227 cm ^-1 (w), 1187 cm ^-1 (w), 1165 cm ^-1 (w), 1103 cm ^-1 (w), 1084 cm ^-1 (w), 1068 cm ^-1 (s), 1051 cm ^-1 (w ), 946 cm ^-1 (w), 929 cm ^-1 (w), 790 cm ^-1 (m), 627 cm ^-1 (w), 616 cm ^-1 (w), 598 cm ^-1 (w), 542 cm ^-1 (m), 524 cm ^-1 (m), 490 cm ^-1 (w).

Claims (8)

3-acetylaminopropane-1-sulfonic acid, characterized by the following characteristic lattice spacing represented by 表, obtained by X-ray crystal diffraction using Cu-Kα1 rays (λ = 1.54Å) Calcium crystal form II.

3-acetylaminopropane-1-sulfonic acid, characterized by the following characteristic lattice spacing represented by 表, obtained by X-ray crystal diffraction using Cu-Kα1 rays (λ = 1.54Å) Calcium crystal form II.

3-acetylamino-1-calcium sulphonate containing crystalline form II according to claim 1 or 2. 3-acetylamino-1-calcium sulphonate which consists essentially of the crystalline form II according to claim 1 or 2.   3. Crystal form according to claim 1 or 2, characterized in that the crystal of crystalline form I of calcium 3-acetylaminopropane-1-sulfonate is stirred in a dispersion medium and the resulting residue is separated and dried. Preparation method of II.   3. Crystal form according to claim 1 or 2 as a medicament.   A pharmaceutical composition comprising the crystalline form II according to claim 1 or 2 and one or more adjuvants.   Use of crystalline form II according to claim 1 or 2 for the preparation of a medicament.

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